Significance Simian immunodeficiency virus infection of newborn and infant macaques is a useful animal model of human AIDS to evaluate the antiviral effects and toxicity of novel antiviral drugs such as 9-[2-(Phosphonomethoxy)-propyl]adenine (PMPA). Objectives To evaluate the long-term therapeutic and toxic effects PMPA in SIV-infected newborn rhesus macaques. Results Four untreated SIV-infected newborn macaques developed persistently high viremia and three of the 4 animals had rapidly fatal disease within 3 months. In contrast, long-term PMPA treatment of 4 newborn macaques, starting 3 weeks after virus inoculation, resulted in a rapid, pronounced and persistent reduction of viremia in three of the four animals. Emergence of virus with 5-fold decreased susceptibility to PMPA occurred in all 4 PMPA-treated animals and was associated with the development of a K65R mutation and additional mutations in reverse transcriptase; however, the clinical implications of this low-level drug resistance are unclear, as three of the 4 animals are currently still alive at 2.5 years. Following prolonged PMPA treatemt (> 1-2 years), the development of toxicity was observed; this seemed to be associated with a reduced clearance of PMPA. For these animals, a PMPA dosage reduction to one third seems to be sufficient to make toxicity disappear, without apparant loss of antiviral effects. Our data suggest that PMPA holds much promise for the treatment of HIV-infected human infants and adults. Future Directions A longer follow-up will further determine the long-term therapeutic effects of prolonged PMPA treatment. Because PMPA is currently in phase I/II human trials (where the longest treatment period so far has been 4 weeks), results from our animals which have been on PMPA for almost 3 years are very useful. In other studies, we have determined the virulence of the PMPA-resistant SIV mutants by inoculation into new animals.. KEYWORDS primate, therapy pathogenesis, drug resistance, pediatrics